Original Observations and Research Personal Observation: Intravenous Aminophylline Treatment for Migraine Michael Kenyon MD, Barry Phillips MD, Christiaan DeWit MBBCh About the Authors Michael Kenyon (near right) and Barry Phillips (far right) are internists, and Christiaan De Wit is an emergency room physician, all practising at Mills Memorial Hospital, in Terrace, British Columbia. Correspondence may be directed to: [email protected] igraine is common condition, often affecting young inhibitor and adenosine antagonist. It has been shown in Mpatients and causing disruption in the home and dipyridamole (Persantine) MIBI studies that dipyridamole workplace alike. The impact of patients presenting to administration inhibits adenosine deaminase in red-cell emergency room services with intractable headache is membranes, increasing blood levels of adenosine. This induces significant, often tying up space and resources in the tedious coronary vasodilation through a low-affinity interaction with wait for a narcotic and sedative “cure.” In Canada alone, 3.2 the A2a receptor. The antidote, aminophylline, preferentially million adults suffer from migraines, and the condition costs binds to this receptor, displacing adenosine and curtailing its the Canadian economy an estimated $500 million annually. effect. 3,4 Absenteeism and loss of productivity resulting from migraines Aminophylline has traditionally and principally been used cost $20 every second. 1 as an intravenously or orally administered bronchodilator in Mills Memorial Hospital is a regional referral centre in asthmatics. Caution in its use should be observed in patients Terrace, British Columbia, serving a population of 70,000 with active peptic ulceration, a low seizure threshold, people. Between June 2011 and January 2012, 21 patients came hypokalemia, tachyarrhythmias, and acute congestive heart to the emergency room (ER) suffering from symptoms failure (CHF). It is contraindicated in acute porphyria and in compatible with migraine headache as defined by International patients with a sensitivity to methylxanthine products. 10,11 Headache Society criteria. 2 These patients had failed to achieve In keeping with our practice in the cardiodiagnostic results from standard outpatient therapy, and the internal laboratory, we monitored the electrocardiograms (ECGs) and medicine service was consulted. blood pressures of all patients during the administration of this We care for patients in the ER and the intensive care unit drug. For safety, all treatments were administered in a (ICU): we also supervise patients undergoing nuclear monitored setting to patients under direct observation in the cardiology testing (stress and dipyridamole methoxyiso- ER by nursing and physician staff. 4 butylisonitrile [MIBI]). As such, we have experience in the Often, migraine patients presenting to the ER have tried administration of intravenous (IV) dipyridamole, an arterial various standard therapies, including antiemetics, analgesics, vasodilator that can induce a vascular headache in 20% of caffeine/ergot preparations, triptans, beta blockers, subjects. Standard therapy for this common side effect is the acetaminophen-codeine preparations, and nonsteroidal anti- administration of 50–250 mg (usual dose = 100 mg) of IV inflammatory agents. It is common for these patients to receive aminophylline, given by IV push over a 30- to 60-second parenteral narcotics and antiemetics and be cared for in a dark, period. 3,4 This protocol almost always brings about rapid and quiet room for several hours in an otherwise-busy ER. 12 persistent relief of headache, without significant adverse effects. 4 Methods We postulated that the administration of IV aminophylline We report 21 cases observed over a 7-month period; all of these would be effective in the treatment of the vasodilatory patients attended the ER. Each patient met the International component of spontaneous migraine complex. 5–9 Amino- Headache Society criteria for migraine headache 2 and had failed phylline is a competitive non-selective phosphodiesterase standard outpatient therapy with conventional treatments. All Canadian Journal of General Internal Medicine Volume 7, Issue 4, Winter 2012 129 Intravenous Aminophylline Treatment for Migraine underwent a complete history and physical examination and Tech 2009;37(1):14–25. had an appropriate laboratory profile performed. We explained 4. American Society of Nuclear Cardiology. Imaging guidelines for nuclear cardiology procedures: a report of the American Society of Nuclear the rationale of aminophylline treatment and our experience Cardiology Quality Assurance Committee. J Nucl Cardiol 2006;13(6):e21– with it as a safe, readily available treatment for dipyridamole- 171. induced vascular headache in our most medically frail cardiac 5. Burnstock G. Pathophysiology of migraine: a new hypothesis. Lancet 1981;317(8235):1397–9. patients. All gave informed consent to this modest dose of a safe 6. Gureu R, Devaux C, Henry H, et al. Adenosine and migraine. Can J Neurol and well-known therapeutic agent, albeit for the unlabelled Sci 1998;25(1):55–8. indication of spontaneous migraine outside of the Nuclear 7. Winn HR, Morii S, Berne R. The role of adenosine in autoregulation. Ann Biomedical Eng 1985;13(3–4):321–8. Medicine Laboratory. 8. Charles A. Advances in the basic and clinical science of migraine. Ann Neurol 2009;65(5):491. Results and Discussion 9. Peterson EC, Wang Z, Britz G. Regulation of cerebral blood flow. Int J Vasc Med 2011;106–16. Aminophylline is a cheap, genericized, readily available 10. Aminophylline. Wikipedia, The Free Encyclopedia, 2012; medication with known pharmacokinetic properties. It has not http://en.wikipedia.org/wiki/Aminophylline. been studied as an IV therapy for refractory migraine. An 11. Repchinsky C, Welbanks L et al., eds. Theophyllines. CPS 2012;2641–2. 12. Edmeads J, Findlay H, Tugwell P, et al. A Canadian population survey on extensive literature review on Google, Medline, and PubMed the clinical, epidemiologic and societal impact of migraine and tension- confirmed this. (We did get interesting “hits” for its use in post– type headache on lifestyle, consulting behaviour, and medication use: a lumbar puncture headache 13 and in “myocardial migraine.” 14 ) In Canadian population survey. Can J Neurol Sci 1993;20:131–7. 13. Frank RL. Lumbar puncture and post-dural puncture headaches: this observation of 21 patients, aminophylline proved to be a implications for the emergency physician. J Emerg Med 2008;35(2): highly effective intervention. After the completion of a 20-minute 149–57. infusion of aminophylline, 17 of 21 patients had a substantial or 14. Michel C, Lisbona R, Derbekyan V, et al. Report of a patient with complete relief of their headache and were fit for discharge from syndrome X due to excessive adenosine effect: myocardial migraine without myocardial ischemia Can J Cardiol 1995;11(4):339–44. the ED, two were felt to have treatment failure, and two had partial relief. We noted that patients with localizing symptoms and signs did well uniformly. (Our sample size was small, but this Appendix: Case Reports was also something more objective to measure.) As this was an observational study, it did not incorporate Case 1 formal long-term follow-up interviews with this patient group; S.M. was a 40-year-old female migraineur of many years. On however, we have not been made aware of any subsequent her 3rd day of “usual, severe migraine,” and unresponsive to a adverse outcome by our family or ER doctors or at follow-up range of standard therapies, she experienced a rapid, significant chart reviews (computerized, regional), and there is an (80–90%) relief of the headache with 100 mg aminophylline impression that there is reduced “rebound effect” compared with IV over 20 minutes. The relief was dramatic and rapid, with several other standard therapies. nausea and photophobia completely cured immediately before We believe our experience with this inexpensive, safe, and the infusion was finished. There were no side effects. She was easily accessible medication offers promise for a formal able to return to work immediately post-treatment. randomized double-blind trial in a sizable cohort of migraine She subsequently had a second episode, identically relieved patients. Oral and suppository routes for aminophylline therapy by the same treatment, except that the aminophylline was for migraine might also be explored. We hope that this approach infused over 10 minutes. Once again, she was able to return to might afford prompt relief of symptoms for a difficult-to-treat work, unlike with other treatments she has tried in the past. condition, and may allow early and safe discharge from congested She has also observed that the frequency of episodes has ERs. We feel that a randomized, double-blind, controlled trial is diminished after these treatments, as compared to previous indicated, with the approval of our local ethics board. experience (no “rebound” phenomenon). References Case 2 1. Lamoureaux, V. Migraine facts and statistics. Kirkland (QC): Merck Frosst Canada,n.d.; http://www.ebookbrowse.com/backgrounder-migraine-final- P.L. was a 52-year-old female homemaker with frequent pdf-d20740949. Accessed February 25, 2013. hemiplegic migraine, complex migraine; she was a frequent 2. Headache Classification Subcommittee of the International Headache recipient of narcotics. Presenting with a hemiplegic episode Society. The international classification of headache disorders, 2nd edition.